Pyrroloquinoline quinone ameliorates renal fibrosis in diabetic nephropathy by inhibiting the pyroptosis pathway in C57BL/6 mice and human kidney 2 cells.

Abstract

Diabetic nephropathy (DN), which is characterized by renal fibrosis, is a major complication of diabetes, a disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis is an essential signaling pathway in DN-related injuries, such as renal fibrosis. Pyrroloquinoline quinone (PQQ) is a naturally occurring bioactive compound that protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused by high glucose concentrations. However, the nature and underlying mechanism of the effect of PQQ on DN-related renal fibrosis remains unclear. In this study, we evaluated whether PQQ has potential protective effects against renal fibrosis due to DN by establishing type 1 diabetes in mice via streptozotocin treatment and then inhibiting their pyroptosis signaling pathway. We found that compared to control mice, the area of renal fibrosis and injury were significantly increased in diabetic mice, and this was accompanied by increased levels of expression of collagen Ⅰ and transforming growth factor-β1; increased concentrations of the inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; and activation of the pyroptosis pathway components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1β, and IL-18. All of these changes were reversed by PQQ treatment. Analogously, we treated cultured HK-2 cells with a high concentration of glucose (35 mmol/L), which caused these cells to exhibit significantly increased concentrations of reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-κB), p-IkappaB, NLRP3, caspase-1, IL-1β, and IL-18, and the loss of mitochondrial transmembrane potential. However, PQQ treatment significantly blunted these effects. In conclusion, in this study we demonstrated that PQQ attenuates renal fibrosis by alleviating mitochondrial dysfunction, reducing ROS production, and inhibiting the activation of the NF-κB/pyroptosis pathway under conditions of DN and hyperglycemia.

• Authors: Xuefeng Qu, Bingzhong Zhai, Yifeng Liu, Yihao Chen, Zemi Xie, Qinxi Wang, Yuejin Wu, Zhen Liu, Jianguo Chen, Song Mei, Jie Wu, Zhenqiang You, Yongjie Yu, Yin Wang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 150 Pg. 112998 (Jun 2022) ISSN: 1950-6007 [Electronic] France
• PMID: 35489281 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Interleukin-18
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species
• PQQ Cofactor
• Caspase 1
• Glucose

Topics

• Animals
• Caspase 1
• Diabetes Mellitus, Experimental (complications, drug therapy, metabolism)
• Diabetic Nephropathies (metabolism)
• Fibrosis
• Glucose (pharmacology)
• Humans
• Interleukin-18
• Kidney
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• PQQ Cofactor (pharmacology, therapeutic use)
• Pyroptosis
• Reactive Oxygen Species (metabolism)